Background: Locally-advanced rectal cancer (LARC) remains a clinical challenge with few improvements noted over the past few decades. Although immunotherapy has no current clinical role in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can induce neoantigen presentation, modulate the microenvironment, and improve the likelihood of immunogenic activation with checkpoint inhibitor use. This prospective phase II study will test that hypothesis in addition to confirming safety of this approach using a “window-of-opportunity” study design with the anti-PDL1 agent durvalumab (MEDI4736). Methods: This multi-center phase II trial is currently enrolling patients (pts) with rectal cancer who are undergoing standard NCCN guideline-compliant NAC and RT. Eligibility includes pts with MSS stage II-IV rectal cancer with adequate organ function and pre-treatment diagnostic tumor available for profiling who are undergoing NAC with intentions to proceed to surgical resection. Stage IV disease must be limited such that the primary pelvic tumor requires definitive management. Standard ineligibility criteria include active infections, systemic steroid use, or other conditions making immunotherapy use unsafe. Treatment includes durvalumab (750mg IV infusion once every 2 wks) for 4 total doses beginning within 3-7 days after NAC completion. Surgery must be within 8-12 wks of the final RT dose. Primary endpoint is a demonstrated improvement in Neoadjuvant Rectal Cancer (NAR) score compared to historical controls representing a 20% relative risk reduction in DFS HR and 3-4% absolute OS improvement. Secondary endpoints include comparisons of OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, off-target “abscopal” effects for the subset of stage IV pts, and exploratory assessments of tumor infiltrating lymphocytes, circulating immunologic profiles, and molecular predictors of response. A safety run-in portion of the study will precede full enrollment. Enrollment continues to 47 total pts to achieve 41 surgically evaluable pts. Support: AstraZeneca-Medimmune, NSABP Foundation Clinical trial information: NCT03102047